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Genetic Basis and Genetic Modifiers of β-Thalassemia and Sickle Cell Disease

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Book cover Gene and Cell Therapies for Beta-Globinopathies

Part of the book series: Advances in Experimental Medicine and Biology ((ASGCT,volume 1013))

Abstract

β-thalassemia and sickle cell disease (SCD) are prototypical Mendelian single gene disorders, both caused by mutations affecting the adult β-globin gene. Despite the apparent genetic simplicity, both disorders display a remarkable spectrum of phenotypic severity and share two major genetic modifiers—α-globin genotype and innate ability to produce fetal hemoglobin (HbF, α2γ2).

This article provides an overview of the genetic basis for SCD and β-thalassemia, and genetic modifiers identified through phenotype correlation studies. Identification of the genetic variants modifying HbF production in combination with α-globin genotype provide some prediction of disease severity for β-thalassemia and SCD but generation of a personalized genetic risk score to inform prognosis and guide management requires a larger panel of genetic modifiers yet to be discovered.

Nonetheless, genetic studies have been successful in characterizing some of the key variants and pathways involved in HbF regulation, providing new therapeutic targets for HbF reactivation.

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References

  1. Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 2008 Jun;86(6):480-7. PubMed PMID: 18568278.

    Google Scholar 

  2. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010 Jun 3;115(22):4331-6. PubMed PMID: 20233970. Pubmed Central PMCID: 2881491. Epub 2010/03/18. eng.

    Google Scholar 

  3. Thein SL. The Molecular Basis of beta-Thalassemia. Cold Spring Harb Perspect Med. 2013;3(5):3/5/a011700 [pii] 10.1101/cshperspect.a. PubMed PMID: 23637309. Epub 2013/05/03. eng.

    Google Scholar 

  4. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet. 2010 Dec 11;376(9757):2018-31. PubMed PMID: 21131035. Epub 2010/12/07. eng.

    Google Scholar 

  5. Willcox M. The haemoglobin pattern of sickle cell and haemoglobin C b+-thalassaemia in Liberia. Journal of Medical Genetics. 1983;20:430-2.

    Google Scholar 

  6. Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Williams TN, et al. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat Commun. 2010;1:104. PubMed PMID: 21045822. Pubmed Central PMCID: 3060623. Epub 2010/11/04. eng.

    Google Scholar 

  7. Piel FB, Patil AP, Howes RE, Nyangiri OA, Gething PW, Dewi M, et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet. 2013 Jan 12;381(9861):142-51. PubMed PMID: 23103089. Pubmed Central PMCID: 3547249. Epub 2012/10/30. eng.

    Google Scholar 

  8. Stamatoyannopoulos G. Control of globin gene expression during development and erythroid differentiation. Experimental hematology. 2005 Mar;33(3):259-71. PubMed PMID: 15730849.

    Google Scholar 

  9. Carter D, Chakalova L, Osborne CS, Dai YF, Fraser P. Long-range chromatin regulatory interactions in vivo. Nature genetics. 2002;32(4):623-6. PubMed PMID: 12426570.

    Google Scholar 

  10. Li Q, Peterson KR, Fang X, Stamatoyannopoulos G. Locus control regions. Blood. 2002;100(9):3077-86. PubMed PMID: 12384402.

    Google Scholar 

  11. Palstra RJ, de Laat W, Grosveld F. Beta-globin regulation and long-range interactions. Adv Genet. 2008;61:107-42. PubMed PMID: 18282504.

    Google Scholar 

  12. Cantor AB, Orkin SH. Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene. 2002 May 13;21(21):3368-76. PubMed PMID: 12032775.

    Google Scholar 

  13. Bauer DE, Orkin SH. Update on fetal hemoglobin gene regulation in hemoglobinopathies. Curr Opin Pediatr. 2011 Feb;23(1):1-8. PubMed PMID: 21157349. Pubmed Central PMCID: 3092400. Epub 2010/12/16. eng.

    Google Scholar 

  14. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis. 2010;5:11. PubMed PMID: 20492708. Pubmed Central PMCID: 2893117. Epub 2010/05/25. eng.

    Google Scholar 

  15. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes. 4th ed. Oxford: Blackwell Science; 2001.

    Google Scholar 

  16. Serjeant GR. The natural history of sickle cell disease. In: Weatherall DJ, Schechter AN, Nathan DG, editors. Hemoglobin and its diseases. Cold Spring Harbor Perspectives in Medicine. New York: Cold Spring Harbor Laboratory Press; 2013. p. 301-11.

    Google Scholar 

  17. Kiefer CM, Hou C, Little JA, Dean A. Epigenetics of beta-globin gene regulation. Mutat Res. 2008 Dec 1;647(1-2):68-76. PubMed PMID: 18760288. Pubmed Central PMCID: 2617773. Epub 2008/09/02. eng.

    Google Scholar 

  18. Hanscombe O, Whyatt D, Fraser P, Yannoutsos N, Greaves D, Dillon N, et al. Importance of globin gene order for correct developmental expression. Genes and Development. 1991;5:1387-94.

    Google Scholar 

  19. Raich N, Enver T, Nakamoto B, Josephson B, Papayannopoulou T, Stamatoyannopoulos G. Autonomous developmental control of human embryonic globin gene switching in transgenic mice. Science. 1990;250:1147-9.

    Google Scholar 

  20. Dillon N, Grosveld F. Human g-globin genes silenced independently of other genes in the b-globin locus. Nature. 1991;350:252-4.

    Google Scholar 

  21. Thein SL, Wood WG. The molecular basis of β-thalassemia, δβ-thalassemia, and hereditary persistence of fetal hemoglobin. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, editors. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Second ed. Cambridge, UK: Cambridge University Press; 2009. p. 323-56.

    Google Scholar 

  22. Giardine B, Borg J, Higgs DR, Peterson KR, Philipsen S, Maglott D, et al. Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach. Nature genetics. 2011 Apr;43(4):295-301. PubMed PMID: 21423179. Epub 2011/03/23. eng.

    Google Scholar 

  23. Huisman THJ. Levels of Hb A2 in heterozygotes and homozygotes for beta-thalassemia mutations: Influence of mutations in the CACCC and ATAAA motifs of the beta-globin gene promoter. Acta haematologica. 1997;98:187-94. PubMed PMID: 9401495.

    Google Scholar 

  24. Moi P, Faa V, Marini MG, Asunis I, Ibba G, Cao A, et al. A novel silent beta-thalassemia mutation in the distal CACCC box affects the binding and responsiveness to EKLF. British journal of haematology. 2004 Sep;126(6):881-4. PubMed PMID: 15352994.

    Google Scholar 

  25. Miller IJ, Bieker JJ. A novel, erythroid cell-specific murine transcription factor that binds to the CACCC element and is related to the Krüppel family of nuclear proteins. Molecular and cellular biology. 1993;13(5):2776-86.

    Google Scholar 

  26. Perkins AC, Sharpe AH, Orkin SH. Lethal b-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF. Nature. 1995;375(6529):318-22.

    Google Scholar 

  27. Nuez B, Michalovich D, Bygrave A, Ploemacher R, Grosveld F. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature. 1995;375(6529):316-8.

    Google Scholar 

  28. Bieker JJ. Erythroid-specific transcription. Current opinion in hematology. 1998;5:145-50.

    Google Scholar 

  29. Bieker JJ. Putting a finger on the switch. Nature genetics. 2010 Sep;42(9):733-4. PubMed PMID: 20802474. Epub 2010/08/31. eng.

    Google Scholar 

  30. Siatecka M, Bieker JJ. The multifunctional role of EKLF/KLF1 during erythropoiesis. Blood. 2011 Aug 25;118(8):2044-54. PubMed PMID: 21613252. Pubmed Central PMCID: 3292426. Epub 2011/05/27. eng.

    Google Scholar 

  31. Yien YY, Bieker JJ. EKLF/KLF1, a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination. Molecular and cellular biology. 2013 Jan;33(1):4-13. PubMed PMID: 23090966. Pubmed Central PMCID: 3536305. Epub 2012/10/24. eng.

    Google Scholar 

  32. Menzel S, Garner C, Gut I, Matsuda F, Yamaguchi M, Heath S, et al. A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15. Nature genetics. 2007 Oct;39(10):1197-9. PubMed PMID: 17767159.

    Google Scholar 

  33. Uda M, Galanello R, Sanna S, Lettre G, Sankaran VG, Chen W, et al. Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. Proceedings of the National Academy of Sciences of the United States of America. 2008 Feb 5;105(5):1620-5. PubMed PMID: 18245381.

    Google Scholar 

  34. Sankaran VG, Menne TF, Xu J, Akie TE, Lettre G, Van Handel B, et al. Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A. Science. 2008 Dec 19;322(5909):1839-42. PubMed PMID: 19056937.

    Google Scholar 

  35. Sankaran VG, Xu J, Ragoczy T, Ippolito GC, Walkley CR, Maika SD, et al. Developmental and species-divergent globin switching are driven by BCL11A. Nature. 2009 Aug 27;460(7259):1093-7. PubMed PMID: 19657335.

    Google Scholar 

  36. Xu J, Peng C, Sankaran VG, Shao Z, Esrick EB, Chong BG, et al. Correction of Sickle Cell Disease in Adult Mice by Interference with Fetal Hemoglobin Silencing. Science. 2011 Nov 18;334(6058):993-6. PubMed PMID: 21998251. Epub 2011/10/15. eng.

    Google Scholar 

  37. Borg J, Papadopoulos P, Georgitsi M, Gutierrez L, Grech G, Fanis P, et al. Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin. Nature genetics. 2010 Aug 1;42(9):801-5. PubMed PMID: 20676099. Epub 2010/08/03. Eng.

    Google Scholar 

  38. Zhou D, Liu K, Sun CW, Pawlik KM, Townes TM. KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching. Nature genetics. 2010 Sep;42(9):742-4. PubMed PMID: 20676097. Epub 2010/08/03. Eng.

    Google Scholar 

  39. Arnaud L, Saison C, Helias V, Lucien N, Steschenko D, Giarratana MC, et al. A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia. American journal of human genetics. 2010 Nov 12;87(5):721-7. PubMed PMID: 21055716. Pubmed Central PMCID: 2978953. Epub 2010/11/09. eng.

    Google Scholar 

  40. Borg J, Patrinos GP, Felice AE, Philipsen S. Erythroid phenotypes associated with KLF1 mutations. Haematologica. 2011 May;96(5):635-8. PubMed PMID: 21531944. Pubmed Central PMCID: 3084906. Epub 2011/05/03. eng.

    Google Scholar 

  41. Jaffray JA, Mitchell WB, Gnanapragasam MN, Seshan SV, Guo X, Westhoff CM, et al. Erythroid transcription factor EKLF/KLF1 mutation causing congenital dyserythropoietic anemia type IV in a patient of Taiwanese origin: review of all reported cases and development of a clinical diagnostic paradigm. Blood cells, molecules & diseases. 2013 Aug;51(2):71-5. PubMed PMID: 23522491. Epub 2013/03/26. eng.

    Google Scholar 

  42. Magor GW, Tallack MR, Gillinder KR, Bell CC, McCallum N, Williams B, et al. KLF1 null neonates display hydrops fetalis and a deranged erythroid transcriptome. Blood. 2015 Feb 27;ePub ahead of print. PubMed PMID: 25724378.

    Google Scholar 

  43. Gonzalez-Redondo JM, Stoming TA, Kutlar A, Kutlar F, Lanclos KD, Howard EF, et al. A C->T substitution at nt -101 in a conserved DNA sequence of the promoter region of the ß-globin gene is associated with 'silent' ß-thalassemia. Blood. 1989;73:1705-11.

    Google Scholar 

  44. Maragoudaki E, Kanavakis E, Trager-Synodinos J, Vrettou C, Tzetis M, Metxotou-Mavrommati A, et al. Molecular, haematological and clinical studies of the -101 C®T substitution in the β-globin gene promoter in 25 β-thalassaemia intermedia patients and 45 heterozygotes. British journal of haematology. 1999;107(4):699-706. PubMed PMID: 10606872.

    Google Scholar 

  45. Wong C, Dowling CE, Saiki RK, Higuchi RG, Erlich HA, Kazazian HHJ. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987;330:384-6.

    Google Scholar 

  46. Safaya S, Rieder RF, Dowling CE, Kazazian HHJ, Adams JGI. Homozygous b-thalassemia without anemia. Blood. 1989;73:324-8.

    Google Scholar 

  47. Huang S-Z, Wong C, Antonarakis SE, Ro-Lein T, Lo WHY, Kazazian HHJ. The same TATA box b-thalassemia mutation in Chinese and US Blacks: Another example of independent origins of mutation. Human Genetics. 1986;74:162-4.

    Google Scholar 

  48. Rund D, Oron-Karni V, Filon D, Goldfarb A, Rachmilewitz E, Oppenheim A. Genetic analysis of ß-thalassaemia intermedia in Israel: diversity of mechanisms and unpredictability of phenotype. American journal of hematology. 1997 Jan;54(1):16-22. PubMed PMID: 8980256.

    Google Scholar 

  49. Orkin SH, Kazazian HHJ, Antonarakis SE, Ostrer H, Goff SC, Sexton JP. Abnormal RNA processing due to the exon mutation of bE-globin gene. Nature. 1982;300:768-9.

    Google Scholar 

  50. Fucharoen S, Weatherall DJ. The hemoglobin E thalassemias. Cold Spring Harb Perspect Med [Internet]. 2012; 2(8):[a011734 p.]. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22908199.

  51. Schoenberg DR, Maquat LE. Regulation of cytoplasmic mRNA decay. Nat Rev Genet. 2012;13(4):246-59. PubMed PMID: 22392217. Epub 2012/03/07. eng.

    Google Scholar 

  52. Hall GW, Thein SL. Nonsense codon mutations in the terminal exon of the ß-globin gene are not associated with a reduction in ß-mRNA accumulation: a mechanism for the phenotype of dominant ß-thalassemia. Blood. 1994;83:2031-7.

    Google Scholar 

  53. Varawalla NY, Old JM, Sarkar R, Venkatesan R, Weatherall DJ. The spectrum of b-thalassaemia mutations on the Indian subcontinent: the basis for prenatal diagnosis. British journal of haematology. 1991;78:242-7.

    Google Scholar 

  54. Andersson BA, Wering ME, Luo HY, Basran RK, Steinberg MH, Smith HP, et al. Sickle cell disease due to compound heterozygosity for Hb S and a novel 7.7-kb beta-globin gene deletion. European journal of haematology. 2007 Jan;78(1):82-5. PubMed PMID: 17038017.

    Google Scholar 

  55. Gilman JG. The 12.6 kilobase DNA deletion in Dutch b0-thalassaemia. British journal of haematology. 1987;67:369-72.

    Google Scholar 

  56. Schokker RC, Went LN, Bok J. A new genetic variant of ß-thalassaemia. Nature. 1966 Jan 1;209:44-6. PubMed PMID: 5925329.

    Google Scholar 

  57. Craig JE, Kelly SJ, Barnetson R, Thein SL. Molecular characterization of a novel 10.3 kb deletion causing beta-thalassaemia with unusually high Hb A2. British journal of haematology. 1992;82(4):735-44.

    Google Scholar 

  58. Thein SL. Structural Variants with a Beta-Thalassemia Phenotype. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, editors. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge,UK: Cambridge University Press, Cambridge,UK; 2001. p. 342-55.

    Google Scholar 

  59. Thein SL. Is it dominantly inherited beta thalassaemia or just a beta-chain variant that is highly unstable? British journal of haematology. 1999 Oct;107(1):12-21. PubMed PMID: 10520021.

    Google Scholar 

  60. Kimberland ML, Divoky V, Prchal J, Schwahn U, Berger W, Kazazian HH, Jr. Full-length human L1 insertions retain the capacity for high frequency retrotransposition in cultured cells. Hum Mol Genet. 1999 Aug;8(8):1557-60. PubMed PMID: 10401005.

    Google Scholar 

  61. Viprakasit V, Gibbons RJ, Broughton BC, Tolmie JL, Brown D, Lunt P, et al. Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy. Hum Mol Genet. 2001;10(24):2797-802. PubMed PMID: 11734544.

    Google Scholar 

  62. Yu C, Niakan KK, Matsushita M, Stamatoyannopoulos G, Orkin SH, Raskind WH. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood. 2002;100(6):2040-5. PubMed PMID: 12200364.

    Google Scholar 

  63. Badens C, Mattei MG, Imbert AM, Lapoumérouliee C, Martini N, Michel G, et al. A novel mechanism for thalassaemia intermedia. The Lancet. 2002;359(9301):132-3. PubMed PMID: 11809258.

    Google Scholar 

  64. Galanello R, Perseu L, Perra C, Maccioni L, Barella S, Longinotti M, et al. Somatic deletion of the normal beta-globin gene leading to thalassaemia intermedia in heterozygous beta-thalassaemic patients. British journal of haematology. 2004 Dec;127(5):604-6. PubMed PMID: 15566365.

    Google Scholar 

  65. Chang JG, Tsai WC, Chong IW, Chang CS, Lin CC, Liu TC. Beta-thalassemia major evolution from beta-thalassemia minor is associated with paternal uniparental isodisomy of chromosome 11p15. Haematologica. 2008 Jun;93(6):913-6. PubMed PMID: 18413893.

    Google Scholar 

  66. Bento C, Maia TM, Milosevic JD, Carreira IM, Kralovics R, Ribeiro ML. beta thalassemia major due to acquired uniparental disomy in a previously healthy adolescent. Haematologica. 2013 Jan;98(1):e4-6. PubMed PMID: 22875618. Pubmed Central PMCID: 3533667. Epub 2012/08/10. eng.

    Google Scholar 

  67. Nagel RL, Steinberg MH. Genetics of the βS Gene: Origins, Genetic Epidemiology, and Epistasis in sickle cell Anemia. In: Steinberg MH, Forget BG, Higgs DR, Nagel RL, editors. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Cambridge,UK: Cambridge University Press, Cambridge,UK; 2001. p. 711-55.

    Google Scholar 

  68. Thein SL. Pathophysiology of Beta Thalassemia--A Guide to Molecular Therapies. Hematology (Am Soc Hematol Educ Program). 2005:31-7. PubMed PMID: 16304356.

    Google Scholar 

  69. Thein SL. Genetic association studies in β-hemoglobinopathies. Hematology ASH Education Program book 2013. 2013 Dec 2013;Dec 2013(1):354-61. PubMed PMID: 24319204. Eng.

    Google Scholar 

  70. Raychaudhuri S. Mapping rare and common causal alleles for complex human diseases. Cell. 2011 Sep 30;147(1):57-69. PubMed PMID: 21962507. Pubmed Central PMCID: 3198013.

    Google Scholar 

  71. Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science. 2008 Nov 7;322(5903):881-8. PubMed PMID: 18988837.

    Google Scholar 

  72. Thein SL, Craig JE. Genetics of Hb F/F cell variance in adults and heterocellular hereditary persistence of fetal hemoglobin. Hemoglobin. 1998;22:401-14.

    Google Scholar 

  73. Garner C, Tatu T, Reittie JE, Littlewood T, Darley J, Cervino S, et al. Genetic influences on F cells and other hematologic variables: a twin heritability study. Blood. 2000;95(1):342-6. PubMed PMID: 10607722.

    Google Scholar 

  74. Thein SL, Menzel S. Discovering the genetics underlying foetal haemoglobin production in adults. British journal of haematology. 2009 May;145(4):455-67. PubMed PMID: 19344402.

    Google Scholar 

  75. Thein SL, Menzel S, Lathrop M, Garner C. Control of fetal hemoglobin: new insights emerging from genomics and clinical implications. Hum Mol Genet. 2009 Oct 15;18(R2):R216-23. PubMed PMID: 19808799.

    Google Scholar 

  76. Sankaran VG, Xu J, Orkin SH. Advances in the understanding of haemoglobin switching. British journal of haematology. 2010 Apr;149(2):181-94. PubMed PMID: 20201948.

    Google Scholar 

  77. Labie D, Pagnier J, Lapoumeroulie C, Rouabhi F, Dunda-Belkhodja O, Chardin P, et al. Common haplotype dependency of high G gamma-globin gene expression and high Hb F levels in beta-thalassemia and sickle cell anemia patients. Proceedings of the National Academy of Sciences, USA. 1985 Apr;82(7):2111-4. PubMed PMID: 2580306. Pubmed Central PMCID: 397502. Epub 1985/04/01.

    Google Scholar 

  78. Nagel RL, Fabry ME, Pagnier J, Zohoun I, Wajcman H, Baudin V, et al. Hematologically and genetically distinct forms of sickle cell anemia in Africa. The Senegal type and the Benin type. New England Journal of Medicine. 1985 Apr 4;312(14):880-4. PubMed PMID: 2579336.

    Google Scholar 

  79. Nagel RL, Rao SK, Dunda-Belkhodja O, Connolly MM, Fabry ME, Georges A, et al. The hematologic characteristics of sickle cell anemia bearing the Bantu haplotype: the relationship between Gg and Hb F level. Blood. 1987;69:1026-30.

    Google Scholar 

  80. Lettre G, Sankaran VG, Bezerra MA, Araujo AS, Uda M, Sanna S, et al. DNA polymorphisms at the BCL11A, HBS1L-MYB, and beta-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease. Proceedings of the National Academy of Sciences of the United States of America. 2008 Aug 19;105(33):11869-74. PubMed PMID: 18667698.

    Google Scholar 

  81. Galanello R, Sanna S, Perseu L, Sollaino MC, Satta S, Lai ME, et al. Amelioration of Sardinian beta-zero thalassemia by genetic modifiers. Blood. 2009 Oct 29;114(18):3935-7. PubMed PMID: 19696200.

    Google Scholar 

  82. Bhatnagar P, Purvis S, Barron-Casella E, Debaun MR, Casella JF, Arking DE, et al. Genome-wide association study identifies genetic variants influencing F-cell levels in sickle-cell patients. Journal of human genetics. 2011 Apr;56(4):316-23. PubMed PMID: 21326311. Epub 2011/02/18. eng.

    Google Scholar 

  83. Makani J, Menzel S, Nkya S, Cox SE, Drasar E, Soka D, et al. Genetics of fetal hemoglobin in Tanzanian and British patients with sickle cell anemia. Blood. 2011 Jan 27;117(4):1390-2. PubMed PMID: 21068433. Epub 2010/11/12. eng.

    Google Scholar 

  84. Badens C, Joly P, Agouti I, Thuret I, Gonnet K, Fattoum S, et al. Variants in genetic modifiers of beta-thalassemia can help to predict the major or intermedia type of the disease. Haematologica. 2011 Nov;96(11):1712-4. PubMed PMID: 21791466. Pubmed Central PMCID: 3208691. Epub 2011/07/28. eng.

    Google Scholar 

  85. Bae HT, Baldwin CT, Sebastiani P, Telen MJ, Ashley-Koch A, Garrett M, et al. Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans. Blood. 2012 Aug 30;120(9):1961-2. PubMed PMID: 22936743. Pubmed Central PMCID: 3433099. Epub 2012/09/01. eng.

    Google Scholar 

  86. Mtatiro SN, Singh T, Rooks H, Mgaya J, Mariki H, Soka D, et al. Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania. PloS one. 2014;9(11):e111464. PubMed PMID: 25372704. Pubmed Central PMCID: 4221031.

    Google Scholar 

  87. Viprakasit V, Ekwattanakit S, Riolueang S, Chalaow N, Fisher C, Lower K, et al. Mutations in Kruppel-like factor 1 cause transfusion-dependent hemolytic anemia and persistence of embryonic globin gene expression. Blood. 2014 Jan 17. PubMed PMID: 24443441. Epub 2014/01/21. Eng.

    Google Scholar 

  88. Liu D, Zhang X, Yu L, Cai R, Ma X, Zheng C, et al. KLF1 mutations are relatively more common in a thalassemia endemic region and ameliorate the severity of beta-thalassemia. Blood. 2014 Jul 31;124(5):803-11. PubMed PMID: 24829204. Pubmed Central PMCID: 4118488.

    Google Scholar 

  89. Esteghamat F, Gillemans N, Bilic I, van den Akker E, Cantu I, van Gent T, et al. Erythropoiesis and globin switching in compound Klf1::Bcl11a mutant mice. Blood. 2013 Mar 28;121(13):2553-62. PubMed PMID: 23361909. Epub 2013/01/31. eng.

    Google Scholar 

  90. Bauer DE, Kamran SC, Lessard S, Xu J, Fujiwara Y, Lin C, et al. An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science. 2013 Oct 11;342(6155):253-7. PubMed PMID: 24115442. Epub 2013/10/12. eng.

    Google Scholar 

  91. Jawaid K, Wahlberg K, Thein SL, Best S. Binding patterns of BCL11A in the globin and GATA1 loci and characterization of the BCL11A fetal hemoglobin locus. Blood cells, molecules & diseases. 2010 Aug 15;45(2):140-6. PubMed PMID: 20542454.

    Google Scholar 

  92. Xu J, Sankaran VG, Ni M, Menne TF, Puram RV, Kim W, et al. Transcriptional silencing of {gamma}-globin by BCL11A involves long-range interactions and cooperation with SOX6. Genes & development. 2010 Apr 15;24(8):783-98. PubMed PMID: 20395365.

    Google Scholar 

  93. Xu J, Bauer DE, Kerenyi MA, Vo TD, Hou S, Hsu YJ, et al. Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A. Proceedings of the National Academy of Sciences of the United States of America. 2013 Apr 16;110(16):6518-23. PubMed PMID: 23576758. Pubmed Central PMCID: 3631619. Epub 2013/04/12. eng.

    Google Scholar 

  94. Thein SL, Menzel S, Peng X, Best S, Jiang J, Close J, et al. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proceedings of the National Academy of Sciences of the United States of America. 2007 Jul 3;104(27):11346-51. PubMed PMID: 17592125.

    Google Scholar 

  95. Stadhouders R, Aktuna S, Thongjuea S, Aghajanirefah A, Pourfarzad F, van Ijcken W, et al. HBS1L-MYB intergenic variants modulate fetal hemoglobin via long-range MYB enhancers. The Journal of clinical investigation. 2014 Apr;124(4):1699-710. PubMed PMID: 24614105. Pubmed Central PMCID: 3973089.

    Google Scholar 

  96. Menzel S, Rooks H, Zelenika D, Mtatiro SN, Gnanakulasekaran A, Drasar E, et al. Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP-2. Annals of human genetics. 2014 Jul 29. PubMed PMID: 25069958. Pubmed Central PMCID: 4303951.

    Google Scholar 

  97. Stadhouders R, Thongjuea S, Andrieu-Soler C, Palstra RJ, Bryne JC, van den Heuvel A, et al. Dynamic long-range chromatin interactions control Myb proto-oncogene transcription during erythroid development. The EMBO journal. 2012 Feb 15;31(4):986-99. PubMed PMID: 22157820. Pubmed Central PMCID: 3280550. Epub 2011/12/14. eng.

    Google Scholar 

  98. Suzuki M, Yamazaki H, Mukai HY, Motohashi H, Shi L, Tanabe O, et al. Disruption of the Hbs1l-Myb locus causes hereditary persistence of fetal hemoglobin in a mouse model. Molecular and cellular biology. 2013 Apr;33(8):1687-95. PubMed PMID: 23428869. Pubmed Central PMCID: 3624254. Epub 2013/02/23. eng.

    Google Scholar 

  99. Farrell JJ, Sherva RM, Chen ZY, Luo HY, Chu BF, Ha SY, et al. A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression. Blood. 2011 May 5;117(18):4935-45. PubMed PMID: 21385855. Pubmed Central PMCID: 3100700. Epub 2011/03/10. eng.

    Google Scholar 

  100. Bianchi E, Zini R, Salati S, Tenedini E, Norfo R, Tagliafico E, et al. c-Myb supports erythropoiesis through the transactivation of KLF1 and LMO2 expression. Blood. 2010 Nov 25;116(22):e99-110. PubMed PMID: 20686118. Epub 2010/08/06. Eng.

    Google Scholar 

  101. Tallack MR, Perkins AC. Three fingers on the switch: Kruppel-like factor 1 regulation of gamma-globin to beta-globin gene switching. Current opinion in hematology. 2013 May;20(3):193-200. PubMed PMID: 23474875. Epub 2013/03/12. eng.

    Google Scholar 

  102. Menzel S, Jiang J, Silver N, Gallagher J, Cunningham J, Surdulescu G, et al. The HBS1L-MYB intergenic region on chromosome 6q23.3 influences erythrocyte, platelet, and monocyte counts in humans. Blood. 2007 Nov 15;110(10):3624-6. PubMed PMID: 17712044.

    Google Scholar 

  103. Soranzo N, Spector TD, Mangino M, Kuhnel B, Rendon A, Teumer A, et al. A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium. Nature genetics. 2009 Nov;41(11):1182-90. PubMed PMID: 19820697.

    Google Scholar 

  104. van der Harst P, Zhang W, Mateo Leach I, Rendon A, Verweij N, Sehmi J, et al. Seventy-five genetic loci influencing the human red blood cell. Nature. 2012 Dec 20;492(7429):369-75. PubMed PMID: 23222517. Epub 2012/12/12. eng.

    Google Scholar 

  105. Menzel S, Garner C, Rooks H, Spector TD, Thein SL. HbA2 levels in normal adults are influenced by two distinct genetic mechanisms. British journal of haematology. 2013 Jan;160(1):101-5. PubMed PMID: 23043469. Epub 2012/10/10. eng.

    Google Scholar 

  106. Welch JJ, Watts JA, Vakoc CR, Yao Y, Wang H, Hardison RC, et al. Global regulation of erythroid gene expression by transcription factor GATA-1. Blood. 2004 Nov 15;104(10):3136-47. PubMed PMID: 15297311.

    Google Scholar 

  107. Sankaran VG, Menne TF, Scepanovic D, Vergilio JA, Ji P, Kim J, et al. MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13. Proceedings of the National Academy of Sciences of the United States of America. 2011 Jan 25;108(4):1519-24. PubMed PMID: 21205891. Pubmed Central PMCID: 3029749. Epub 2011/01/06. eng.

    Google Scholar 

  108. Huehns ER, Hecht F, Keil JV, Motulsky AG. Developmental hemoglobin anomalies in a chromosomal triplication: D1 trisomy syndrome. Proc Natl Acad Sci USA. 1964 Jan;51:89-97. PubMed PMID: 14104609. Pubmed Central PMCID: 300609. Epub 1964/01/01. eng.

    Google Scholar 

  109. Sankaran VG, Joshi M, Agrawal A, Schmitz-Abe K, Towne MC, Marinakis N, et al. Rare complete loss of function provides insight into a pleiotropic genome-wide association study locus. Blood. 2013 Nov 28;122(23):3845-7. PubMed PMID: 24288412. Epub 2013/11/30. eng.

    Google Scholar 

  110. Galarneau G, Palmer CD, Sankaran VG, Orkin SH, Hirschhorn JN, Lettre G. Fine-mapping at three loci known to affect fetal hemoglobin levels explains additional genetic variation. Nature genetics. 2010 Nov 7;40(12):1049-51. PubMed PMID: 21057501. Epub 2010/11/09. Eng.

    Google Scholar 

  111. Suzuki M, Yamamoto M, Engel JD. Fetal globin gene repressors as drug targets for molecular therapies to treat the beta-globinopathies. Molecular and cellular biology. 2014 Oct 1;34(19):3560-9. PubMed PMID: 25022757. Pubmed Central PMCID: 4187729.

    Google Scholar 

  112. Amin BR, Bauersachs RM, Meiselman HJ, Mohandas N, Hebbel RP, Bowen PE, et al. Monozygotic twins with sickle cell anemia and discordant clinical courses: clinical and laboratory studies. Hemoglobin. 1991;15(4):247-56. PubMed PMID: 1723971.

    Google Scholar 

  113. Joishy SK, Griner PF, Rowley PT. Sickle b-thalassemia: identical twins differing in severity implicate nongenetic factors influencing course. American journal of hematology. 1976;1(1):23-33. PubMed PMID: 988745.

    Google Scholar 

  114. Weatherall MW, Higgs DR, Weiss H, Weatherall DJ, Serjeant GR. Phenotype/genotype relationships in sickle cell disease: a pilot twin study. Clin Lab Haematol. 2005 Dec;27(6):384-90. PubMed PMID: 16307540.

    Google Scholar 

  115. Noguchi CT, Torchia DA, Schechter AN. Intracellular polymerization of sickle hemoglobin. Effects of cell heterogeneity. The Journal of clinical investigation. 1983 Sep;72(3):846-52. PubMed PMID: 6886006. Pubmed Central PMCID: 1129249.

    Google Scholar 

  116. Serjeant GR, Serjeant BE. Sickle Cell Disease. Third ed. Oxford, UK: Oxford University Press; 2001. 772 p.

    Google Scholar 

  117. Bonham VL, Dover GJ, Brody LC. Screening student athletes for sickle cell trait--a social and clinical experiment. The New England journal of medicine. 2010 Sep 9;363(11):997-9. PubMed PMID: 20825310. Epub 2010/09/10. eng.

    Google Scholar 

  118. Noguchi CT, Rodgers GP, Serjeant G, Schechter AN. Levels of fetal hemoglobin necessary for treatment of sickle cell disease. New England Journal of Medicine. 1988;318(2):96-9. PubMed PMID: 2447498.

    Google Scholar 

  119. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease: Life expectancy and risk factors for early death. New England Journal of Medicine. 1994;330(23):1639-44.

    Google Scholar 

  120. Wang WC, Pavlakis SG, Helton KJ, McKinstry RC, Casella JF, Adams RJ, et al. MRI abnormalities of the brain in one-year-old children with sickle cell anemia. Pediatric blood & cancer. 2008 Nov;51(5):643-6. PubMed PMID: 18478575.

    Google Scholar 

  121. Thein SL. Genetic modifiers of sickle cell disease. Hemoglobin. 2011;35(5-6):589-606. PubMed PMID: 21967611. Epub 2011/10/05. eng.

    Google Scholar 

  122. Steinberg MH, Sebastiani P. Genetic modifiers of sickle cell disease. American journal of hematology. 2012 Aug;87(8):795-803. PubMed PMID: 22641398. Epub 2012/05/30. eng.

    Google Scholar 

  123. Wonkam A, Ngo Bitoungui VJ, Vorster AA, Ramesar R, Cooper RS, Tayo B, et al. Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon. PloS one. 2014;9(3):e92506. PubMed PMID: 24667352. Pubmed Central PMCID: 3965431.

    Google Scholar 

  124. Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, editors. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Second ed. Cambridge,UK: Cambridge University Press, Cambridge,UK; 2009.

    Google Scholar 

  125. Vasavda N, Menzel S, Kondaveeti S, Maytham E, Awogbade M, Bannister S, et al. The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease. British journal of haematology. 2007 Jul;138(2):263-70. PubMed PMID: 17593033.

    Google Scholar 

  126. Rumaney MB, Ngo Bitoungui VJ, Vorster AA, Ramesar R, Kengne AP, Ngogang J, et al. The co-inheritance of alpha-thalassemia and sickle cell anemia is associated with better hematological indices and lower consultations rate in Cameroonian patients and could improve their survival. PloS one. 2014;9(6):e100516. PubMed PMID: 24978191. Pubmed Central PMCID: 4076272.

    Google Scholar 

  127. Serjeant GR, Higgs DR, Hambleton IR. Elderly survivors with homozygous sickle cell disease. The New England journal of medicine. 2007 Feb 8;356(6):642-3. PubMed PMID: 17287491.

    Google Scholar 

  128. Vasavda N, Badiger S, Rees D, Height S, Howard J, Thein SL. The presence of alpha-thalassaemia trait blunts the response to hydroxycarbamide in patients with sickle cell disease. British journal of haematology. 2008 Nov;143(4):589-92. PubMed PMID: 18764867.

    Google Scholar 

  129. Castro OL, Gordeuk VR, Gladwin MT, Steinberg MH. Senicapoc trial results support the existence of different sub-phenotypes of sickle cell disease with possible drug-induced phenotypic shifts. British journal of haematology. 2011 Dec;155(5):636-8. PubMed PMID: 21732927. Epub 2011/07/08. eng.

    Google Scholar 

  130. Fertrin KY, Costa FF. Genomic polymorphisms in sickle cell disease: implications for clinical diversity and treatment. Expert Rev Hematol. 2010 Aug;3(4):443-58. PubMed PMID: 21083035. Epub 2010/11/19. eng.

    Google Scholar 

  131. Milton JN, Sebastiani P, Solovieff N, Hartley SW, Bhatnagar P, Arking DE, et al. A genome-wide association study of total bilirubin and cholelithiasis risk in sickle cell anemia. PloS one. 2012;7(4):e34741. PubMed PMID: 22558097. Pubmed Central PMCID: 3338756. Epub 2012/05/05. eng.

    Google Scholar 

  132. Heeney MM, Howard TA, Zimmerman SA, Ware RE. UGT1A promoter polymorphisms influence bilirubin response to hydroxyurea therapy in sickle cell anemia. J Lab Clin Med. 2003 Apr;141(4):279-82. PubMed PMID: 12677174.

    Google Scholar 

  133. Flanagan JM, Sheehan V, Linder H, Howard TA, Wang YD, Hoppe CC, et al. Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia. Blood. 2013 Apr 18;121(16):3237-45. PubMed PMID: 23422753. Epub 2013/02/21. eng.

    Google Scholar 

  134. Flanagan JM, Frohlich DM, Howard TA, Schultz WH, Driscoll C, Nagasubramanian R, et al. Genetic predictors for stroke in children with sickle cell anemia. Blood. 2011 Jun 16;117(24):6681-4. PubMed PMID: 21515823. Pubmed Central PMCID: 3123027. Epub 2011/04/26. eng.

    Google Scholar 

  135. Castro V, Alberto FL, Costa RN, Lepikson-Neto J, Gualandro SF, Figueiredo MS, et al. Polymorphism of the human platelet antigen-5 system is a risk factor for occlusive vascular complications in patients with sickle cell anemia. Vox sanguinis. 2004 Aug;87(2):118-23. PubMed PMID: 15355504.

    Google Scholar 

  136. Sebastiani P, Solovieff N, Hartley SW, Milton JN, Riva A, Dworkis DA, et al. Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study. American journal of hematology. 2010 Jan;85(1):29-35. PubMed PMID: 20029952. Epub 23 Oct 2009.

    Google Scholar 

  137. Milton JN, Rooks H, Drasar E, McCabe EL, Baldwin CT, Melista E, et al. Genetic determinants of haemolysis in sickle cell anaemia. British journal of haematology. 2013 Apr;161(2):270-8. PubMed PMID: 23406172. Epub 2013/02/15. eng.

    Google Scholar 

  138. Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 2010 Jul 1;115(26):5300-11. PubMed PMID: 20223921. Pubmed Central PMCID: 2902131. Epub 2010/03/13. eng.

    Google Scholar 

  139. Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA : the journal of the American Medical Association. 2014 Sep 10;312(10):1033-48. PubMed PMID: 25203083.

    Google Scholar 

  140. Ware RE, Eggleston B, Redding-Lallinger R, Wang WC, Smith-Whitley K, Daeschner C, et al. Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy. Blood. 2002;99(1):10-4. PubMed PMID: 11756146.

    Google Scholar 

  141. Ho PJ, Hall GW, Luo LY, Weatherall DJ, Thein SL. Beta thalassemia intermedia: is it possible to consistently predict phenotype from genotype? British journal of haematology. 1998;100(1):70-8.

    Google Scholar 

  142. So CC, Song YQ, Tsang ST, Tang LF, Chan AY, Ma ES, et al. The HBS1L-MYB intergenic region on chromosome 6q23 is a quantitative trait locus controlling fetal haemoglobin level in carriers of beta-thalassaemia. J Med Genet. 2008 Nov;45(11):745-51. PubMed PMID: 18697826.

    Google Scholar 

  143. Nuinoon M, Makarasara W, Mushiroda T, Setianingsih I, Wahidiyat PA, Sripichai O, et al. A genome-wide association identified the common genetic variants influence disease severity in β0-thalassemia/hemoglobin E. Hum Genet. 2010 March;127(3):303-14. PubMed PMID: 19924444.

    Google Scholar 

  144. Sedgewick AE, Timofeev N, Sebastiani P, So JC, Ma ES, Chan LC, et al. BCL11A is a major HbF quantitative trait locus in three different populations with beta-hemoglobinopathies. Blood cells, molecules & diseases. 2008 Nov-Dec;41(3):255-8. PubMed PMID: 18691915.

    Google Scholar 

  145. Danjou F, Anni F, Perseu L, Satta S, Dessi C, Lai ME, et al. Genetic modifiers of beta-thalassemia and clinical severity as assessed by age at first transfusion. Haematologica. 2012 Jul;97(7):989-93. PubMed PMID: 22271886. Pubmed Central PMCID: 3396667.

    Google Scholar 

  146. Danjou F, Francavilla M, Anni F, Satta S, Demartis FR, Perseu L, et al. A genetic score for the prediction of beta-thalassemia severity. Haematologica. 2014 Dec 5. PubMed PMID: 25480500.

    Google Scholar 

  147. Harteveld CL, Higgs DR. α-thalassaemia. Orphanet Journal of Rare Diseases. 2010 May 2010;5(Item 13):21.

    Google Scholar 

  148. Weiss MJ, dos Santos CO. Chaperoning erythropoiesis. Blood. 2009 Mar 5;113(10):2136-44. PubMed PMID: 19109556.

    Google Scholar 

  149. Danjou F, Anni F, Galanello R. Beta-thalassemia: from genotype to phenotype. Haematologica. 2011 Nov;96(11):1573-5. PubMed PMID: 22058279. Pubmed Central PMCID: 3208672. Epub 2011/11/08. eng.

    Google Scholar 

  150. Thein SL. Genetic modifiers of the beta-haemoglobinopathies. British journal of haematology. 2008 May;141(3):357-66. PubMed PMID: 18410570.

    Google Scholar 

  151. Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004 Apr 30;117(3):285-97. PubMed PMID: 15109490.

    Google Scholar 

  152. Nagel RL, Fabry ME, Steinberg MH. The paradox of hemoglobin SC disease. Blood reviews. 2003 Sep;17(3):167-78. PubMed PMID: 12818227.

    Google Scholar 

  153. Masiello D, Heeney MM, Adewoye AH, Eung SH, Luo HY, Steinberg MH, et al. Hemoglobin SE disease: a concise review. American journal of hematology. 2007 Jul;82(7):643-9. PubMed PMID: 17278112.

    Google Scholar 

  154. Moo-Penn W, Bechtel K, Jue D, Chan MS, Hopkins G, Schneider NJ, et al. The presence of hemoglobin S and C Harlem in an individual in the United States. Blood. 1975 Sep;46(3):363-7. PubMed PMID: 1148394.

    Google Scholar 

  155. Monplaisir N, Merault G, Poyart C, Rhoda MD, Craescu C, Vidaud M, et al. Hemoglobin S antilles: A variant with lower solubility than hemoglobin S and producing sickle cell disease in heterozygotes. Proceedings of the National Academy of Sciences of the United States of America. 1986 Dec;83(24):9363-7. PubMed PMID: 3467311.

    Google Scholar 

  156. Witkowska HE, Lubin BH, Beuzard Y, Baruchel S, Esseltine DW, Vichinsky EP, et al. Sickle cell disease in a patient with sickle cell trait and compound heterozygosity for hemoglobin S and hemoglobin Quebec-Chori. The New England journal of medicine. 1991 Oct 17;325(16):1150-4. PubMed PMID: 1891024.

    Google Scholar 

  157. Steinberg MH. Other sickle hemoglobinopathies. In: Steinberg MH, Forget BG, Higgs DR, Weatherall DJ, editors. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. Second ed. Cambridge,UK: Cambridge University Press, Cambridge,UK; 2009. p. 564-86.

    Google Scholar 

  158. Geva A, Clark JJ, Zhang Y, Popowicz A, Manning JM, Neufeld EJ. Hemoglobin Jamaica plain--a sickling hemoglobin with reduced oxygen affinity. The New England journal of medicine. 2004 Oct 7;351(15):1532-8. PubMed PMID: 15470216.

    Google Scholar 

  159. Nagel RL, Daar S, Romero JR, Suzuka SM, Gravell D, Bouhassira E, et al. HbS-Oman heterozygote: A new dominant sickle syndrome. Blood. 1998;92:4375-82.

    Google Scholar 

  160. Swensen JJ, Agarwal AM, Esquilin JM, Swierczek S, Perumbeti A, Hussey D, et al. Sickle cell disease due to uniparental disomy in a child who inherited sickle cell trait. Blood. 2010 Oct 14;116(15):2822-5. Epub July 1, 2010.

    Google Scholar 

  161. Koenig SC, Becirevic E, Hellberg MS, Li MY, So JC, Hankins JS, et al. Sickle cell disease caused by heterozygosity for Hb S and novel LCR deletion: Report of two patients. American journal of hematology. 2009 Sep;84(9):603-6. PubMed PMID: 19650141.

    Google Scholar 

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Acknowledgement

I thank Claire Steward for help with preparation of the manuscript.

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  1. Sickle Cell Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Building 10, Room 6S241 MSC 1589, 10 Center Dr., Bethesda, MD, 20892-1589, USA

    Swee Lay Thein

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  1. Cincinnati Children’s Hospital, Comprehensive Sickle Cell Program, Cincinnati, Ohio, USA

    Punam Malik

  2. National Institutes of Health and Human Services, Bethesda, Maryland, USA

    John Tisdale

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Thein, S.L. (2017). Genetic Basis and Genetic Modifiers of β-Thalassemia and Sickle Cell Disease. In: Malik, P., Tisdale, J. (eds) Gene and Cell Therapies for Beta-Globinopathies. Advances in Experimental Medicine and Biology(), vol 1013. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-7299-9_2

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